Tumor is a kind of disease marked by cell malignant proliferation, having a complicated pathogenesis which often involves in heredity or epigenetic changes. The occurrence and development of tumor depend on a variety of receptors or signal transduction pathways, making the antineoplastic drugs which act on certain target point have to face following problems as: 1) The tumor cells cannot be fully killed; 2) it is easy to have drug resistance. Currently, although multi-drug combination has solved the above problems, it is likely to cause interactions between drugs, generating unpredictable adverse reactions; moreover, the usage of each drug in the combination is different from that for separate use. Compared with the drug combination, the multi-target drug can avoid interactions between drugs and have obviously better treatment effect than that of single-target drug.
In recent years, as the studies on malignant tumor are deepened constantly, more and more tumor signal pathways are found. Among which, the antineoplastic protocols with the signal transduction pathway mediated by PI3K as the target point gradually become a study hotspot. The important role of PI3K/Akt/mTOR signal pathway played in the occurrence and development of tumors has been proven in many studies and its function in lung cancer and liver cancer also has been reported.
Histone deacetylases (HDACs) are closely related to tumor; through deacetylation of histone N-lysine residues, gene transcription regulating and chromatin remodeling can be realized. In addition, HDACs can also catalyze non-histone deacetylation, such as p21, microtubulin, HSP90 (heat shock protein 90), etc. Inhibiting HDACs may induce cycle arrest, differentiation and apoptosis of tumor cells.
PI3K protein kinase and HDAC are the most important target points for tumor cell survival; HDAC inhibitor may have inhibition effect on tumor cell messenger multiple target points through epigenetic regulatory mechanism. The significant anti-cancer effect of PI3K inhibitor and HDAC inhibitor has been verified clinically. Multiple HDAC inhibitors as vorinostat (SAHA), panobinostat (LBH589) and chidamide have come into the market upon approval.
Based on the structure characteristics of PI3K kinase inhibitor GDC-0941, Qian C G et al. used the method of pharmacophore splicing, i.e., splicing the pharmacophores of PI3K kinase inhibitor and HDACIs inhibitor into a molecule. Through a great deal of in vivo/in vitro screening, the most preferred compound CUDC-907 is found. It can potently inhibit PI3Ks enzyme of Type I and HDAC enzyme of Type I & II, and its inhibition values to activities of HDAC1, HDAC2, HDAC3, HDAC8, HDAC6, HDAC10, HDAC11, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ are respectively 1.7, 5.0, 1.8, 191, 27, 2.8, 5.4, 19, 54, 39 and 311 nM[1]. The subsequent pharmacology experiment shows that, multiple signal pathways are decreased by inhibiting HDAC through CUDC-907 and the tumor cell growth is thus inhibited. For its favorable subsequent performance, Curis declared on Apr. 6, 2015 that FDA has granted CUDC-907 the qualification of orphan drug for treating diffuse large b-cell lymphoma. Such progress also promotes and encourages the research and development of DAC-kinase multi-target inhibitors.

However, currently there are no related reports to difunctional kinase inhibitors having the biochemical structure of purinyl-N-hydroxyl pyrimidine formamide derivative.